The long-term goal of this research program is to identify the mechanisms of carcinogenesis by nickel compounds. The specific aims of this proposal are: (a) to elucidate the mechanisms of manganese inhibition of the carcinogenicity of nickel subsulfide (alphaNi3S2) and other nickel compounds; (b) to investigate differences in the relative carcinogenicities of several nickel compounds and to identify the metabolic basis for the pronounced differences which have been found between the carcinogenicity of alphaNi3S2 and amorphous nickel monosulfide (NiS); (c) to exploit the unique characteristics of an experimental system for induction of renal cancers by intrarenal injection of alphaNi3S2 by establishing the relationship between alphaNi3S2-stimulation of erythropoietin production and the subsequent development of cancers; and (d) to employ a new technique for intrarenal implantation of alphaNi3S2 within semipermeable tubes to determine the effects of alphaNi3S2 upon RNA- and DNA-polymerase activities and upon the rates of DNA and RNA synthesis. The methods include: (a) carcinogenesis tests in Fischer rats; (b) hematological measurements (e.g., 59 Fe incorporation into erythrocytes and serum erythropoietin activity): and (c) biochemical measurements (e.g., incorporation of 14C-and 3H-labelled precursors into renal DNA and RNA). This study will provide new knowledge and concepts of fundamental importance to metal carcinogenesis and will also furnish information that is useful for assessment of human carcinogenic hazards from environmental and occupational exposures to nickel compounds.